3,5-Di hydroxy morpholine derivatives and pharmaceutical compositions

ABSTRACT

3,5-Di hydroxy morpholine derivatives having antitumor activity and methods of preparation thereof, are disclosed.

This invention relates to new morpholine derivatives. More particularly,this invention relates to new morpholine derivatives andpharmaceutically acceptable salt thereof which have antitumor activity,processes for preparation thereof, a pharmaceutical compositioncomprising the same and method of use thereof.

Accordingly, one object of this invention is to provide the new anduseful morpholine derivatives and pharmaceutically acceptable saltthereof.

Another object of this invention is to provide processes for preparationof the morpholine derivatives and pharmaceutically acceptable saltsthereof.

A further object of this invention is to provide a pharmaceuticalcomposition comprising said morpholine derivative or pharmaceuticallyacceptable salt thereof as an antitumor agent.

Still further object of this invention is to provide a method of usingsaid morpholine derivative or a pharmaceutically acceptable salt thereoffor therapeutic treatment of cancer.

The morpholine derivatives of this invention are novel and representedby the following general formula (I): ##STR1## wherein R¹ is aheterocyclic group selected from uracilyl, cytosinyl, hypoxanthinyl,adeninyl and thiazolyl, which may be substituted with halogen orcarbamoyl,

R² is an N-containing unsaturated heterocyclic group which may besubstituted with oxo or lower alkyl, and

R³ is a hydrogen atom or a phosphono group.

Suitable examples and illustrations for the above definitions areexplained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unlessotherwise indicated.

The heterocyclic group for R¹ is uracilyl, cytosinyl, hypoxanthinyl,adeninyl or thiazolyl, and these heterocyclic groups may be substitutedwith halogen [e.g. fluorine, chlorine, bromine or iodine] or carbamoyl.

Suitable examples of the heterocyclic group having such substituent(s)may be halogenated heterocyclic group such as 5-fluorouracilyl,5-chlorouracilyl, 5-bromouracilyl, 6-fluorouracilyl, 6-chlorouracilyl,5-fluorocytosinyl, 5-chlorocytosinyl, 6-fluorocytosinyl,2-fluorohypoxanthinyl, 8-chlorohypoxanthinyl, 8-chloroadeninyl,2-chlorothiazolyl, carbamoyl substituted heterocyclic group such as2-carbamoylthiazolyl, 4-carbamoylthiazolyl, or the like.

The N-containing unsaturated heterocyclic group for R² means unsaturatedmonocyclic or polycyclic group containing at least one nitrogen atom.

Suitable examples of the heterocyclic group for R² may be unsaturated 3-to 9-membered, preferably 5- or 6-membered, monocyclic heterocyclicgroup containing 1 to 4 nitrogen atom(s) such as pyrrolyl, imidazolyl,pyrazolyl, triazolyl, [e.g. 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl,2H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, etc.], tetrazolyl [e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.], pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl or the like; unsaturated fused heterocyclic group containing1 to 4 nitrogen atom(s) such as indolyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, purinyl or the like; unsaturated 3- to 9-membered,preferably 5- or 6-membered, monocyclic heterocyclic group containing 1to 4 nitrogen atom(s) and 1 to 2 sulfur or oxygen atom(s) such asthiazolyl, isothiazolyl, thiadiazolyl [e.g. 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.],thiazolinyl, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] or the like.

The above-mentioned heterocyclic groups for R² may be substituted withoxo or lower alkyl [e.g. methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.]. Suitable examplesof the heterocyclic group having such substituent(s) may be2-methylthiazolyl, 5-methyloxazolyl, hypoxanthinyl or the like.

Suitable pharmaceutically acceptable salts of the object compounds (I)are conventional non-toxic salts and include a metal salt such as analkali metal salt [e.g. sodium salt, potassium salt, etc.] and analkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], anammonium salt, an organic base salt [e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.], an organic acid salt[e.g. formate, acetate, trifluoroacetate, maleate, tartrate,methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], aninorganic acid salt [e.g. hydrochloride, hydrobromide, sulfate,phosphate, etc.], a salt with an amino acid [e.g. arginine salt,ornithine salt, etc.], and the like.

The object compounds (I) and their salts of the present invention can beprepared by the following processes. ##STR2## wherein R¹, R² and R³ areeach as defined above.

The processes for preparing the object compounds (I) and salts thereofare explained in detail in the following.

Process 1

The object compound (I) and its salt can be prepared by reacting acompound (II) or its salt with a compound (III) or its salt.

Suitable salts of the compounds (II) and (III) may be the same as thoseexemplified for the compound (I).

This reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, propanol, etc.],tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide or anyother organic solvent which does not adversely influence the reaction,or a mixture thereof.

This reaction is preferably conducted in the presence of an acid such asinorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, polyphosphoric acid, etc.], organic acid [e.g. aceticacid, trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid,etc.] or the like. In case that the acid to be used in liquid, it can bealso used as a solvent.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature or under warming.

Process 2

The object compound (I) and its salt can be prepared by reacting acompound (IV) or its salt with a compound (III) or its salt in thepresence of an oxidizing agent.

Suitable salts of the compounds (IV) and (III) may be the same as thoseexemplified for the compound (I).

Suitable oxidizing agent of this reaction may include conventional onesas used in oxidation of 1,2-diol function such as periodic acid or itssalt [e.g. metaperiodic acid, sodium metaperiodate, potassiummetaperiodate, paraperiodic acid, sodium paraperiodate, potassiumparaperiodate, etc.], lead compound [e.g. lead tetraacetate, leadtetrabenzoate etc.], chromic acid or its salt [e.g. sodium dichromate,potassium dichromate, etc.] or the like.

This reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, t-butyl alcohol, etc.], dioxane,acetic acid or any other organic solvent which does not adverselyinfluence the reaction, or a mixture thereof.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

The starting compounds (II) include known compounds described inCARBOHYDRATE RESEARCH 1977, 54(1), 75-84, CANCER RESEARCH 1980, 40(3),598-603, etc., and new compounds. The new starting compounds can beprepared by following method. ##STR3## wherein R ¹ and R³ are each asdefined above.

The compound (II) and its salt can be prepared by oxidizing a compound(IV) or its salt.

Suitable oxidizing agents of this reaction are the same as thoseexemplified in the explanation of Process 2.

This reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, t-butyl alcohol, etc.], dioxane,acetic acid, or a mixture thereof, and these solvents may be selectedaccording to the kind of the oxidizing agent to be used. The reactiontemperature is not critical, and the reaction is usually carried outunder cooling to warming.

The compound (II) can be isolated by a conventional manner such asion-exchange resin column, lyophilization or the like, but it canoptionally be used in the next step, i.e. Process 1, without isolation.

It is to be noted that each of the object compound (I) and the startingcompounds (II), (III) and (IV) include one or more stereoisomers due toasymmetric carbon atoms in the molecule and tautomers, and all of suchisomers of the compound (I), (II), (III) and (IV) are included withinthe scope of this invention.

The new morpholine derivatives (I) and pharmaceutically acceptable saltsthereof possess an antitumor activity, and are useful for a therapeutictreatment of cancer.

For the purpose of showing pharmacological activity of the objectcompounds (I), test data on antitumor activity are illustrated in thefollowing.

Test Method

Six male B D F₁ mice, aged more than 6 weeks, weighing 22.6 g to 25.9 gwere used per group. Lymphocytic Leukemia P388 was transferred every 6or 7 days in DBA/2 mice by intraperitoneal inoculation of ascites cells.Test compounds were dissolved in phosphate buffer serum (PBS). After 24hours of the inoculation of Leukemia cells to the test mice, testcompound was administered intraperitoneally in doses of 32, 56, 100, 320mg/kg, respectively, in each medicated group (PBS only in the controlgroup) once a day for 4 days. Antitumor activity of the test compoundwas evaluated by the increase in life-span over control(ILS=T/C×T/C×100--100) in leukemias, wherein T is medium survival time(MST) of the medicated group, and C is medium survival time of controlgroup.

Test Result

The test results are shown in the following table 1.

                  TABLE 1                                                         ______________________________________                                        Test Compound    Dose                                                         (Example No.)    (mg/kg)  ILS (%)                                             ______________________________________                                        Example 1         32      55                                                                   100      100                                                 Example 2        100      75                                                  Example 3         32      30                                                                   100      85                                                                   320      300                                                 Example 4         32      30                                                                   100      60                                                                   320      90                                                  Example 6         32      30                                                                   100      80                                                  Example 7         32      60                                                                   100      80                                                  Example 8         32      45                                                                   100      70                                                   Example 12       32      46                                                                   100      67                                                   Example 14       32      60                                                                   100      85                                                                   320      295                                                  Example 16       32      55                                                                   100      80                                                  ______________________________________                                    

As being apparent from the above test results, the object compounds (I)of the present invention are useful as an antitumor agent.

For therapeutic administration, the object compound (I) of the presentinvention and pharmaceutically acceptable salts thereof are used in aform of the conventional pharmaceutical preparation in admixture with aconventional pharmaceutically acceptable carrier such as an organic orinorganic solid or liquid excipient which is suitable for oral,parenteral or external administration. The pharmaceutical preparationmay be compounded in a solid form such as capsule, tablet, dragee orsuppository, or in a liquid form such as solution, suspension oremulsion. If needed, there may be included in the above preparationauxiliary substance, stabilizing agent, wetting or emulsifying agent,buffer or any other commonly used additives.

The effective ingredient may usually be administered with a unit dose of1.0 mg/kg to 1000 mg/kg, 1 to 4 times a day. However, the above dosagemay be increased or decreased according to age, weight, conditions ofthe patient or the administering method.

The following examples are given only for the purpose of illustratingthe present invention in more detail.

EXAMPLE 1 ##STR4##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde,(uridinedialdehyde), (2.42 g) was dissolved in a mixture of methanol (50ml) and water (50 ml). To the solution was added2-amino-1,3,4-thiadiazole (1.00 g). The mixture was stirred at ambienttemperature for four hours and evaporated in vacuo. The residue wastriturated with acetone to give 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,3,4-thiadiazol-2-yl)morpholin-2-yl]-uracil(3.0 g).

mp 170°-180° C. (dec.)

IR (Nujol): 3200, 1690 cm⁻¹.

NMR (D₂ O)δ: 3.6-4.5 (3H, m), 5.0-5.7 (2H, m), 5.7-6.2 (2H, m), 7.1-8.1(1H, m), 8.6-9.0 (1H, m).

EXAMPLE 2 ##STR5##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)pyrimidineacetaldehyde,(uridinedialdehyde), (6.05 g) was dissolved in water (25 ml). To asolution was added 2-aminothiazole (2.50 g). The mixture was stirred atambient temperature overnight to give a clear solution. The solution wassubjected to column chromatography on HP-20 resine, which was elutedwith water and then 50% aqueous acetone. The elution was condenced invacuo and lyophilized to give white powder of 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolyl)morpholin-2-yl]uracil(8.09 g).

mp 130°-135° C. (dec.)

IR (Nujol): 3250, 1690 cm⁻¹.

NMR (D₂ O)δ: 3.6-4.5 (3H, m), 5.1-5.8 (2H, m), 5.8-6.2 (2H, m), 6.7-7.5(2H, m), 7.7-8.2 (1H, m).

EXAMPLE 3 ##STR6##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde,(uridinedialdehyde), (6.05 g) was dissolved in water (25 ml). To thesolution was added 2-aminopyrimidine (2.38 g). The mixture was stirredat ambient temperature for eight hours to give a clear solution. Thesolution was lyophilized to give white powder of 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]uracil(8.40 g).

mp 155°-160° C. (dec.)

IR (Nujol): 3300, 1690, 1580 cm⁻¹.

NMR (D₂ O)δ: 3.7-4.4 (3H, m), 5.1-5.5 (1H, m), 5.5-6.4 (3H, m), 6.7-7.2(1H, m), 7.7-8.2 (1H, m), 8.2-8.7 (2H, m).

EXAMPLE 4 ##STR7##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde,(uridinedialdehyde), (4.84 g) was dissolved in a mixture of methanol(100 ml) and water (100 ml). To the solution was added3-amino-1H-1,2,4-triazole (1.68 g). The mixture was stirred at ambienttemperature for five hours and evaporated in vacuo. The residue wastriturated with acetone to give 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,2,4-triazol-3-yl)morpholin-2-yl]uracil(6.25 g).

mp 210° C. (dec.)

IR (Nujol): 3200, 1680 cm⁻¹.

NMR (D₂ O)δ: 3.7-4.5 (3H, m), 5.0-6.5 (4H, m), 7.7-8.5 (2H, m).

EXAMPLE 5 ##STR8##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)pyrimidineacetaldehyde,(uridinedialdehyde), (4.0 g) was dissolved in a mixture of methanol (30ml) and water (30 ml). To the solution was added3-amino-5-methylisoxazole (1.62 g). The mixture was stirred at ambienttemperature for five hours and evaporated in vacuo. The residue wastriturated with acetone to give 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(5-methylisoxazol-3-yl)morpholin-2-yl]uracil(4.2 g).

mp 163°-167° C. (dec.)

IR (Nujol): 3300, 1690, 1620 cm⁻¹.

NMR (D₂ O)δ: 2.1-2.4 (3H, m), 3.6-4.5 (3H, m), 4.9-5.5 (2H, m), 5.5-6.2(3H, m), 7.7-8.2 (1H, m).

EXAMPLE 6 ##STR9##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde,(inosinedialdehyde), (2.66 g) was dissolved in a mixture of methanol(100 ml) and water (100 ml). To the solution was added adenine (1.35 g).The mixture was stirred at ambient temperature for one day and filtered.The filtrate was evaporated in vacuo at 35° C. The residue wastriturated with acetone to give 9-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(6-purinyl)morpholin-2-yl]hypoxanthine(3.20 g).

mp 125°-135° C. (dec.)

IR (Nujol): 3150, 1690, 1590 cm⁻¹.

NMR (D₂ O)δ: 3.6-4.5 (3H, m), 5.0-6.5 (3H, m), 8.0-8.7 (4H, m)

EXAMPLE 7 ##STR10##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde,(inosinedialdehyde), (1.33 g) was dissolved in a mixture of methanol(300 ml) and water (300 ml). To the solution was added guanine (0.76 g).The mixture was stirred at ambient temperature for three days andfiltered. The filtrate was evaporated in vacuo at 35° C. The residue wastriturated with acetone to give 9-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-hypoxanthinyl)morpholin-2-yl]hypoxanthine(2.20 g).

mp 115°-120° C. (dec.)

IR (Nujol): 1310, 1680, 1580 cm⁻¹.

NMR (D₂ O)δ: 3.7-4.5 (3H, m), 5.0-6.3 (3H, m), 8.2-8.8 (3H, m).

EXAMPLE 8 ##STR11##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-4-carbamoyl-2-1,3-thiazoleacetaldehyde(1.10 g) was dissolved in water (30 ml). To the solution was added2-aminopyrimidine (0.41 g). The mixture was stirred at ambienttemperature for five hours to give a clear solution. The solution waslyophilized to give 2-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-4-carbamoylthiazole(1.50 g).

mp 105°-110° C. (dec.)

IR (Nujol): 3320, 1680, 1630, 1580 cm⁻¹.

NMR (D₂ O)δ: 3.5-4.2 (3H, m), 4.5-6.0 (3H, m), 6.7-7.1 (1H, m), 8.1-8.8(3H, m).

EXAMPLE 9 ##STR12##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde,(uridinedialdehyde), (2.4 g) was dissolved in water (10 ml). To thesolution was added 2-amino-2-thiazoline (1.2 g). The mixture was stirredat ambient temperature overnight. An insoluble material was filteredoff. The filtrate was evaporated in vacuo. The residue was trituratedwith acetone to give 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolin-2-yl)morpholin-2-yl]uracil(0.98 g).

IR (Nujol): 3250, 1680 cm⁻¹.

NMR (DMSO-d₆ -D₂ O)δ: 2.7-4.5 (7H, m), 4.5-6.0 (3H, m), 7.3-8.1 (2H, m).

EXAMPLE 10 ##STR13##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde,(uridinedialdehyde), (2.4 g) was dissolved in water (10 ml). To thesolution was added 3-aminopyrazole (0.83 g). The mixture was stirred atambient temperature overnight. The precipitates were filtered andair-dried to give 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(3-pyrazolyl)morpholin-2-yl]uracil(1.25 g).

IR (Nujol): 3250, 1680 cm⁻¹.

NMR (DMSO-d₆ -D₂ O)δ: 2.7-4.6 (3H, m), 4.6-6.5 (3H, m), 7.0-8.0 (4H, m).

EXAMPLE 11 ##STR14##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde,(inosinedialdehyde), (2.6 g) was dissolved in water (25 ml). To thesolution was added 5-aminotetrazole (1.03 g) and stirred at ambienttemperature overnight. The reaction mixture was subjected to columnchromatography on macroporous non-ionic adsorption resin (Diaion HP-20,prepared by Mitsubishi Chem. Ind. Ltd.). The column was eluted withwater.

The eluate was lyophilized to give 9-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(tetrazol-5-yl)-morpholin-2-yl]hypoxanthine(2.0 g).

IR (Nujol): 3200, 1690 cm⁻¹.

NMR (D₂ O)δ: 3.6-4.7 (3H, m), 5.0-6.3 (3H, m), 8.0-8.8 (2H, m).

EXAMPLE 12 ##STR15##

[R-(R*,R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde,(inosinedialdehyde), (2.6 g) was dissolved in water (30 ml). To thesolution was added 2-aminothiazole (1.0 g). The solution was adjusted atpH 5.0 with dilute hydrochloric acid and stirred at ambient temperatureovernight. The precipitate was collected by filtration, washed withacetone and air-dried to give 9-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolyl)morpholin-2-yl]hypoxanthine(2.2 g).

IR (Nujol): 3200, 1700 cm⁻¹.

NMR (DMSO--d₆ --D₂ O)δ: 3.5-5.2 (3H, m), 5.2-6.5 (3H, m), 6.8-7.5 (2H,m), 8.0-8.3 (2H, m).

EXAMPLE 13 ##STR16##

[R-(R*,R*)]-α-(1-Formyl-2-disodiophosphonoethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde,(1.95 g) was dissolved in water (50 ml). To the solution was added2-aminopyrimidine (0.48 g). The solution was stirred at ambienttemperature for 1.3 hours and evaporated in vacuo. The residue wastriturated with acetone and dried over phosphorus pentoxide in vacuo togive 9-[(2R,6R)-3,5-dihydroxy-6-disodiophosphonomethyl-4-(pyrimidin-2-yl)morpholin-2-yl]hypoxanthine(2.1 g).

IR (Nujol): 3200, 1690, 1585 cm⁻¹.

NMR (D₂ O)δ: 3.5-4.7 (3H, m), 5.2-6.5 (3H, m), 6.6-7.1 (1H, m), 7.9-8.8(4H, m).

EXAMPLE 14 ##STR17##

To a solution of cytidine (2.43 g) and 2-aminopyrimidine (0.95 g) inwater (15 ml) was added sodium metaperiodate (2.13 g) at 15° C. Thesolution was stirred at ambient temperature for four hours. To thereaction mixture was added methanol (20 ml). A precipitate was filteredoff and the filtrate was condenced in vacuo. The condenced solution waslyophilized to give white powder of 1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]cytosine(3.20 g).

mp 145°-150° C. (dec.)

IR (Nujol): 3250, 1640, 1580 cm⁻¹.

NMR (D₂ O)δ: 3.7-4.3 (3H, m), 5.1-5.5 (1H, m), 5.5-6.4 (3H, m), 6.7-7.2(1H, m), 7.7-8.2 (1H, m), 8.2-8.7 (2H, m).

EXAMPLE 15 ##STR18##

A solution of sodium metaperiodate (2.13 g) in water (25 ml) was addedto a suspension of adenosine (2.67 g) and 2-aminopyrimidine in water (25ml) at 15° C. The mixture was stirred at ambient temperature for fivehours. To the reaction mixture was added methanol (50 ml). A precipitatewas filtered off and the filtrate was evaporated in vacuo at 35° C. Theresidue was triturated with acetone to give 9-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]adenine(3.64 g).

mp 155°-160° C. (dec.)

IR (Nujol): 3350, 3200, 1640, 1580 cm⁻¹.

NMR (D₂ O)δ: 3.5-4.33 (3H, m), 5.0-6.2 (3H, m), 6.5-7.1 (1H, m), 8.0-8.8(4H, m).

EXAMPLE 16 ##STR19##

To a solution of 5-fluorocytidine (2.42 g) and 2-aminopyrimidine (0.95g) in water (50 ml) was added sodium metaperiodate (2.13 g) undercooling with an ice-water bath. The solution was stirred at ambienttemperature for 8 hours. To the reaction mixture was added methanol (50ml). The precipitate was filtered off and the filtrate was evaporated invacuo. The residue was triturated with acetone and air-dried to give1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-5-fluorocytosine(2.3 g).

IR (Nujol): 3300, 1670, 1580 cm⁻¹.

NMR (D₂ O)δ: 3.6-4.5 (3H, m), 5.0-7.0 (4H, m), 7.5-7.7 (1H, m), 7.7-8.3(2H, m).

What we claim is:
 1. A compound of the formula: ##STR20## wherein R¹ isa heterocyclic group selected from uracilyl, cytosinyl, hypoxanthinyl,adeninyl and thiazolyl, which may be substituted with halogen orcarbamoyl,R² is an N-containing unsaturated heterocyclic group which maybe substituted with oxo or lower alkyl, and R³ is a hydrogen atom or aphosphono group,and pharmaceutically acceptable salts thereof.
 2. Acompound of claim 1, whereinR² is an N-containing unsaturatedheterocyclic group selected from 5 membered ring, 6 membered ring andfused ring comprising 5 and 6 membered rings, which may be substitutedwith oxo or lower alkyl.
 3. A compound of claim 2, whereinR² is anN-containing unsaturated heterocyclic group selected from thiadiazolyl,thiazolyl, thiazolinyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,pyrimidinyl, purinyl and hypoxanthinyl.
 4. A compound of claim 3,whereinR² is thiadiazolyl, thiazolyl, tetrazolyl, pyrimidinyl, purinylor hypoxanthinyl.
 5. A compound of claim 4, whereinR¹ is uracilyl,cytosinyl, hypoxanthinyl, thiazolyl, in which these groups may besubstituted with halogen or carbamoyl.
 6. A compound of claim 5,whereinR¹ is uracilyl optionally substituted with halogen.
 7. A compoundof claim 6, which is1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]uracil.8. A compound of claim 6, which is1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,2,4-triazol-3-yl)morpholin-2-yl]uracil.9. A compound of claim 6, which is1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,3,4-thiadiazol-2-yl)morpholin-2-yl]uracil.10. A compound of claim 5, whereinR¹ is cytosinyl optionally substitutedwith halogen.
 11. A compound of claim 10, which is1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]cytosine12. A compound of claim 10, which is1-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-5-fluorocytosine.13. A compound of claim 5, whereinR¹ is thiazolyl optionally substitutedwith carbamoyl.
 14. A compound of claim 13, which is2-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-4-carbamoylthiazole.15. A compound of claim 5, whereinR¹ is hypoxanthinyl.
 16. A compound ofclaim 15, which is9-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(6-purinyl)morpholin-2-yl]hypoxanthine.17. A compound of claim 15, which is9-[(2R,6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-hypoxanthinyl)morpholin-2-yl]hypoxanthine.18. A pharmaceutical composition comprisng a compound of claim 1, as aneffective ingredient, in association with a pharmaceutically acceptable,substantially nontoxic carrier or excipient.